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Current Zoology 56 (6): 714!727, 2010
Received Jan. 16, 2010; accepted May 10, 2010
" Corresponding author. E-mail: mfh008@bucknell.edu
© 2010 Current Zoology
Telomeres: Linking stress and survival, ecology and evolution
Mark F. HAUSSMANN*, Nicole M. MARCHETTO
Department of Biology, Bucknell University, Lewisburg, PA 17837, USA
Abstract Telomeres are protective structures at the ends of eukaryotic chromosomes. The loss of telomeres through cell divi-
sion and oxidative stress is related to cellular aging, organismal growth and disease. In this way, telomeres link molecular and
cellular mechanisms with organismal processes, and may explain variation in a number of important life-history traits. Here, we
discuss how telomere biology relates to the study of physiological ecology and life history evolution. We emphasize current
knowledge on how telomeres may relate to growth, survival and lifespan in natural populations. We finish by examining interest-
ing new connections between telomeres and the glucocorticoid stress response. Glucocorticoids are often employed as indices of
physiological condition, and there is evidence that the glucocorticoid stress response is adaptive. We suggest that one way that
glucocorticoids impact organismal survival is through elevated oxidative stress and telomere loss. Future work needs to establish
and explore the link between the glucocorticoid stress response and telomere shortening in natural populations. If a link is found,
it provides an explanatory mechanism by which environmental perturbation impacts life history trajectories [Current Zoology 56
(6): 714–727, 2010].
Key words Corticosterone, Stress, Survival, Telomeres
1 Introduction
The birth of telomere biology began with a small
group of scientists studying the functional elements
found at chromosomal ends. But over the past century,
the study of telomeres has moved into the mainstream,
connecting diverse fields like cellular biology, aging,
cancer, ecology and evolution. In 2009, Elizabeth
Blackburn, Carol Greider, and Jack Szostak were
awarded the Nobel Prize in Physiology and Medicine
for the discovery of how chromosomes are protected by
telomeres and the enzyme telomerase. It is not our in-
tention to cover the breadth of telomere biology in this
review, but instead, our goal is to specifically address
how the study of telomeres can provide insight into
ecology and evolutionary biology. The measurement of
telomeres has become a valuable tool in these fields
(Nakagawa et al., 2004; Monaghan et al., 2006), as te-
lomere dynamics are related to survival (Haussmann et
al., 2005; Bize et al., 2009; Salomons et al., 2009), re-
productive success (Pauliny et al., 2006), physiological
stress (Epel et al., 2004; Kotrschal et al., 2007) and
growth (Jennings et al., 1999; Hall et al., 2004).
In this review, we concentrate on the relevance of te-
lomere biology to studies in ecology and evolution. We
begin by briefly outlining telomere structure and func-
tion, and then discuss the main mechanisms by which
telomere length is regulated. We cover both events that
lead to telomere loss and also mechanisms that allow for
telomere restoration. This is followed by a discussion of
how telomeres are related to survival and lifespan,
which focuses heavily on data from wild populations. It
is important to note that currently there is not a consen-
sus on whether telomeres are a cause of aging or merely
a consequence of it (Hornsby, 2006). However, we ex-
plore how telomere measurements provide important
information in ecological studies by serving as a meas-
ure of chronic oxidative stress – a process central to
aging (Finkel et al., 2000) and a mediator of life history
trade-offs (Costantini, 2008; Monaghan et al., 2009).
We finish by highlighting interesting new connections
between telomeres, oxidative stress, and the glucocorti-
coid stress response. While the idea that chronic stress
can accelerate the aging process has permeated geron-
tology for a century, only recently has a link between
chronic stress and cellular aging been established. Be-
cause organisms making their living in the wild experi-
ence a wide range of stressors, telomeres and oxidative
stress may act as an underlying mechanism connecting
the glucocorticoid stress response and survival in natu-
ral populations.
HAUSSMANN MF, MARCHETTO NM: Telomeres, stress and survival 715
2 Telomeres and Oxidative Stress
2.1 The discovery of telomeres and telomeric
function
Gene expression and proper cell functioning depend
upon the maintenance of chromosomal integrity. Early
cytogenetic work in the 1930s by Hermann Muller and
Barbara McClintock showed that chromosomes dama-
ged by X-rays resulted in products of broken chromo-
somes that had joined together. McClintock further ob-
served that the resulting chromosome instability was
detrimental to cells often resulting in cell death. Both
Muller and McClintock discovered that chromosome
products only formed between newly broken ends, but
in no case did a new broken end of one chromosome
attach to the original, intact end of another. This sug-
gested that something was inherently different about the
original ends of chromosomes, and J.B.S. Haldane
named the end of chromosomes the telomere. While
X-rays were used as a tool by early cytogeneticists to
explore chromosome structure by damaging DNA, cells
are naturally bombarded by a number of damaging
agents that can cause DNA double-stranded breaks.
DNA repair machinery recognizes these breaks and
functions to join broken chromosomes back together.
All linear eukaryotic chromosomes then pose a general
problem: how to distinguish between DNA that is a
natural chromosome end and DNA double strand-breaks
that require repair? Although there are many different
solutions to this problem, one of the most ubiquitously
employed is telomeres.
Telomeres are repetitive, non-coding DNA sequences
found at the termini of all linear eukaryotic chromo-
somes. In vertebrates, the telomere sequence is a repeat
of 6 bases rich in guanine (TTAGGG/CCCTAA; Meyne
et al., 1989). While the length of telomeres varies be-
tween chromosomes and species (Aubert et al., 2008),
the sequence is similar across taxa (Bodnar, 2009) sug-
gesting that telomeres are an evolutionarily conserved
system to protect genomic integrity. At the distal end of
the telomere, only the guanine-rich single-strand is pre-
sent, forming a ‘G-strand overhang’. This overhang,
which has variable length on different chromosomes and
in different species (Baird et al., 2003; Aubert et al.,
2008), tucks back into the double-stranded telomere
sequence effectively hiding the terminal tip of the
chromosome in a ‘t-loop’. Chromosomes with suffi-
ciently long telomeres form t-loops and are effectively
‘capped’; it is this structure that prevents telomeric ends
from being mistaken for double-stranded DNA breaks
(di Fagagna et al., 2003). Proper t-loop formation re-
quires 6 telomere-specific proteins called shelterin, and
these proteins ensure that the DNA end is not inappro-
priately processed by DNA repair pathways (de Lange
et al., 1999; Deng et al., 2009). Thus, if telomeres are
long enough to form t-loops with associated shelterin
the chromosomes are capped and protected from
end-to-end fusions that hasten cell death. However, if
telomeres shorten to a critical length, t-loops cannot
form, chromosomes are uncapped, and chromosome
instability and cell death results (Blackburn, 2000). An
important question, then is: what events cause telomere
shortening?
2.2 Telomere dynamics: The balance between
loss and restoration
In the early 1960s, Leonard Hayflick made the dis-
covery that cells in culture would only divide a finite
number of times before ceasing cell division, a process
known as replicative senescence. This led to the hy-
pothesis that telomeres act as a mitotic clock, counting
the number of cell divisions and eventually resulting in
organismal aging and death. While the importance of
replicative senescence to the aging phenomenon is still
debated (Hornsby, 2006), we now know that telomeres
shorten with each replication event, and when telomeres
shorten to a critical length, they induce a permanent
arrest in the cell cycle through a process called cellular
senescence (Hornsby, 2003; Capper et al., 2007). Sub-
stantial evidence is accumulating that telomeres are im-
portant to the aging phenotype (Campisi, 2003; Patil et
al., 2005). For example, senescent cells in vivo secrete
degradative enzymes and inflammatory cytokines that
disrupt nearby cells, contributing to aging and the threat
of cancer (Wu et al., 2003; Campisi, 2005; Capper et al.,
2007). Work in mice has demonstrated that short
telomeres result in multiple organismal defects caused
by defective tissue regeneration (Blasco et al., 1997),
and telomere dysfunction in these mice contributes to
the nonreciprocal translocations that are common in
adult carcinomas (Capper et al., 2007). This pattern is
also seen in human patients who have inherited genetic
defects that limit telomere maintenance increasing their
risk to a number of diseases (Finkel et al., 2007). Fur-
thermore, short telomeres are a risk factor in cardiovas-
cular disease (Samani et al., 2001), liver cirrhosis
(Mason et al., 2005), pulmonary fibrosis (Armanios et
al., 2007), diabetes (Valdes et al., 2005), stroke
(Martin-Ruiz et al., 2006), and Alzheimer’s disease
(Honig et al., 2006).
Because the accumulation of short telomeres predis-
716 Current Zoology Vol. 56 No. 6
poses tissues to cancer and serves as a risk factor for
many diseases, managing the pattern and pace of te-
lomere loss and restoration is critical. Telomere length is
a balance between shortening events (end-replication
problem and oxidative stress) and restoration events
(telomerase and recombination) and the changes in te-
lomere length over time are termed telomere dynamics.
The most relevant processes to telomere dyanmics are
briefly described below.
2.2.1 Telomere loss: The End-replication problem
(Fig. 1) Each time a cell divides; the telomeric DNA
on its chromosomes gets shorter. This is because the
DNA replication machinery cannot completely replicate
the very ends of linear DNA (Fig. 1). This is due to both
the requirement of an RNA primer to allow for poly-
merase to bind and properly function and because DNA
polymerase can only elongate in the 5# $ 3# direction.
In the leading strand, replication is continuous and the
strand is replicated in full. In the lagging strand DNA
replication is discontinuous. At the end of the process
the RNA primer is excised and is replaced with DNA by
polymerase, but on the lagging strand, when the RNA
primer dissociates from the most distal end, DNA po-
lymerase is unable to fill in the gap because there is no
double-stranded region to allow initiation. Thus, during
lagging strand synthesis there is DNA sequence loss
corresponding to where the most distal RNA primer was
laid down. While this results in the generation of the
G-strand overhang (Fig.1g), which is critical for t-loop
formation (Fig. 1h), it also results in loss of telomeric
DNA.
2.2.2 Telomere loss: Oxidative stress Aerobic spe-
cies have evolved the capability of using oxygen for
efficient energy metabolism. A consequence of this
process is the formation of free radicals. While a small
proportion of free radicals serve important functions as
regulating mediators in signaling processing, at higher
concentrations free radicals result in oxidative damage.
Organisms have evolved mechanisms to prevent the
production of free radicals and the oxidative damage
they create on a number of levels.
(i) Changing the proton-motive force across the mi-
tochondrial membrane can alter free radical generation
in the mitochondria. Increasing the proton leak through
the inner mitochondrial membrane via uncoupling pro-
teins results in a net reduction in free radical production
(Hulbert et al., 2007).
(ii) Enzymatic antioxidants located inside of the cell
terminate the chain-reaction of free radicals before it
begins. For example, superoxide dismutase converts
Fig. 1 The DNA end replication problem
A. DNA replication begins at the origin of replication where the dou-
ble stranded helix is unwound by enzymes. B. As the strands separate,
two replication forks form in opposing directions. C. One half of the
replication fork is shown. D. The leading strand demonstrates con-
tinuous replication because DNA polymerase can only synthesize new
DNA in the direction 5#!3#. E. The lagging strand carries out discon-
tinuous replication producing small fragments and requiring multiple
RNA primers. F. After DNA polymerase synthesizes the new frag-
ments, exonuclease must remove the RNA primers and the fragments
are ligated together. G. DNA polymerase is unable to fill in the 5# gap.
H. The g-strand overhang is tucked into a protective t-loop structure.
superoxide, one of the first formed and most potent of
the free radicals, into hydrogen peroxide. Hydrogen
peroxide is also hazardous, but can be converted to wa-
ter by the action of the enzyme catalase (Finkel et al.,
2000).
(iii) Chain-breaking antioxidants neutralize the
spread of free radicals without passing on their reactiv-
ity. This class of antioxidants can be made endogenously,
but many important molecules are acquired through the
diet.
(iv) Despite the aforementioned protection mecha-
nisms some oxidative damage still occurs. A host of
mechanisms in the cell can either repair or destroy and
replace molecules damaged by free radicals (Halliwell
et al., 2007).
With age, however, unrepaired damage accumulates
resulting in disease and increased mortality (Finkel et al.,
HAUSSMANN MF, MARCHETTO NM: Telomeres, stress and survival 717
2000). Oxidative stress, then, can be defined as the bal-
ance between free radicals and antioxidant defense
mechanisms. If free radicals and antioxidants are in
homeostatic balance oxidative stress is low, but if free
radical generation exceeds antioxidant defense, oxida-
tive stress is high resulting in oxidative damage
(Monaghan et al., 2009).
In human cells, telomeres shorten by 50–300 base
pairs per cell division (Harley et al., 1990; Aubert et al.,
2008), but only approximately ten base pairs of this re-
duction is thought to be due to the end-replication prob-
lem (von Zglinicki, 2002). Much of the remaining loss
is caused by oxidative stress. Compared with other re-
gions of DNA, telomeres are particularly vulnerable to
oxidative damage (Rubio et al., 2004; Houben et al.,
2008). This apparently is due both to a relatively high
guanine content (Henle et al., 1999; Oikawa et al., 2001)
and also reduced DNA repair, possibly because shelterin
proteins block DNA repair enzymes (Houben et al.,
2008). Furthermore, oxidative stress exacerbates te-
lomere loss – the amount of unrepaired oxidative dam-
age to the telomeres influences the magnitude of te-
lomere loss at the next cell division (von Zglinicki,
2002). Given that the vast majority of telomere shorten-
ing is a consequence of oxidative stress, these two
proximate cellular aging mechanisms should no longer
be viewed individually but as integral pieces of the lar-
ger aging puzzle (Houben et al., 2008). Telomeres may
act as sentinels of the general level of DNA damage
occurring in the cell. High levels of damage to the te-
lomeres would be indicative of high levels of damage to
the coding sequences. In this way, telomeres provide a
mechanism to ensure that cells with high levels of DNA
damage soon cease division (von Zglinicki, 2003).
2.2.3 Telomere restoration Different taxa possess
different telomere restoration mechanisms. Some
immortalized mammalian cell lines and tumors are able
to maintain telomere length through recombination in a
process termed ALT (Alternative Lengthening of
Telomeres; Dunham et al., 2000; Aubert et al., 2008).
Certain insects, such as Drosophila, utilize transposable
elements to maintain telomere length (Cenci, 2009).
However, the most common form of telomere restora-
tion is through the enzyme telomerase. Telomerase is a
ribonucleoprotein capable of rebuilding and maintaining
telomeres (Greider et al., 1985). The telomerase enzyme
consists of a reverse transcriptase protein (TERT) and a
RNA template component (TERC). Telomerase activity
is regulated at multiple levels including transcription,
alternative splicing, assembly, localization, and post-
translational modification (Hug et al., 2006). Telom-
erase activity in most cell lines is not sufficient to pre-
vent telomere loss (Engelhardt et al., 1997; Lansdorp,
2005), and thus telomeres in tissues like blood cells
shorten with age. Interestingly, oxidative stress also
dramatically decreases TERT activity (Borras et al.,
2004; Kurz et al., 2004) and therefore oxidative stress
not only hastens telomere shortening by direct damage
to telomeres, but also by inhibiting telomere restoration.
While telomerase activity appears to be essential for
telomere maintenance, it is repressed in most normal
adult somatic tissues, probably as a mechanism to pre-
vent tumor growth (Taylor et al., 2000; Parwaresch et al.,
2002).
3 Telomeres and Life History
The concept of trade-offs is central to our under-
standing of the evolution of life histories. Differences
within and among species in life history strategies are
generally framed in terms of differences in the optimal
allocation of resources among growth, reproduction, and
self-maintenance. Identifying mechanisms that underlie
variation in survivorship should provide insight into the
evolution of life history strategies and phenotypic varia-
tion in longevity. Two candidate mechanisms that may
link molecular and cellular mechanisms with organismal
processes such as growth and survival are oxidative
stress (Costantini, 2008; Monaghan et al., 2009) and
telomere dynamics (Monaghan et al., 2006). As dis-
cussed above these two cellular aging mechanisms are
closely connected, and while we focus on telomere dy-
namics below it is important to note that telomeres can
be used as a biomarker for chronic oxidative stress
(Houben et al., 2008). Therefore many of the conclu-
sions we draw about telomeres role in mediating life
history trade-offs is likely to be shared by oxidative
stress. In the following section we explore how telomere
biology may shed light on some of the different proc-
esses that are traded-off against one another from a life
history perspective.
3.1 Telomeres and survival
The relationship between telomere loss and advan-
cing age is well established in vitro and in vivo. Detect-
able telomere shortening has been shown in humans
(Harley et al., 1990; Aubert et al., 2008), non-primate
mammals (Coviello-McLaughlin et al., 1997; Nasir et
al., 2001), birds (Haussmann et al., 2002; Haussmann et
al., 2003b; Haussmann et al., 2008a), reptiles (Scott et
al., 2006), and fish (Hatakeyama et al., 2008; Hartmann
et al., 2009). Most of these studies are cross-sectional in
718 Current Zoology Vol. 56 No. 6
nature, making them subject to cohort effects or selec-
tive mortality (Haussmann et al., 2008b), but data from
longitudinal studies are beginning to accumulate and
confirm the age-related declines in telomere length.
Longitudinal studies also demonstrate that telomere loss
is much faster early in life (Hall et al., 2004; Baerlocher
et al., 2007; Aviv et al., 2009; Salomons et al., 2009),
probably because growth and cell division is most rapid
at this time. Recent work in free-living jackdaws Corvus
monedula showed that within individuals, long te-
lomeres shorten more rapidly than short telomeres re-
gardless of subject age (Salomons et al., 2009). Con-
currently, an unrelated study in humans also showed
that telomere attrition was greatest in individuals with
long telomeres (Nordfjall et al., 2009). Taken together,
the results of these studies suggest that a telomere
maintenance mechanism exists in vivo that preferen-
tially protects the shortest telomeres from further deg-
radation. Even though telomere loss is variable at dif-
ferent ages and in different tissues, the gradual loss of
telomeres with advancing age allows for the possibility
of telomere-based age estimation (Haussmann et al.,
2008a). While this method will never provide com-
pletely precise age estimation, it can provide some in-
formation on age structure in natural populations where
longitudinal data are limited (Haussmann et al., 2003a;
but see Juola et al., 2006).
The big question in the context of life-history trade-
offs is how changes to telomeres at the cellular level
influence organismal survival. As mentioned previously,
telomere loss and restoration have costs and benefits
that need to be balanced. For example, reducing telom-
erase activity can serve as a tumor protective mecha-
nism, but it also hastens cellular senescence. While the
replicative potential of cells in culture is positively cor-
related to the longevity of the species they came from
(Rohme, 1981), data at the organismal level is less clear
(Hornsby, 2002; Hornsby, 2006). In humans studied
over a 20 year period, individuals > 60 years of age with
shorter than average blood cell telomeres had lower
survival, due to higher mortality from heart and infec-
tious disease, than did individuals of the same age with
longer than average blood cell telomeres (Cawthon et al.,
2003). While similar patterns of telomere length and
survival were found in other human studies (Honig et al.,
2006; Bakaysa et al., 2007; Kimura et al., 2007), there is
additional human work that shows no clear association
between telomere length and survival (Martin-Ruiz et
al., 2005; Bischoff et al., 2006; Njajou et al., 2009).
Studies of telomere length and survival are also ac-
cumulating in wild populations. Yearling female tree
swallows Tachycineta bicolor with shorter than average
telomere lengths were less likely to return to the breed-
ing site in subsequent years than those with longer than
average telomere lengths (Haussmann et al., 2005). In
comparison to human studies, this suggests that te-
lomere maintenance is associated with early survival,
and not just late-life mortality. In other avian studies,
individuals with the highest telomere loss rate also have
the lowest likelihood to survive (Pauliny et al., 2006;
Bize et al., 2009; Salomons et al., 2009). A study of al-
pine swifts Tachymarptis melba reported that telomere
dynamics were better predictors of survival than age
(Bize et al., 2009). In addition, work done in free-living
jackdaws Corvus monedula demonstrated that telomere
shortening rate predicted survival, and that rate of te-
lomere shortening was greatly accelerated during an indi-
viduals last year in the colony (Salomons et al., 2009).
Taken together, the studies on human populations and
wild avian populations suggest that the relationship be-
tween telomeres and survival may depend on the age of
the individuals studied. The discrepancy in the human
data may be because these studies focus on individuals
nearing the end of their species maximum lifespan. In
contrast, the avian studies sampled either very young
individuals or individuals across their lifespan. Work in
an extremely long-lived bird, the Leach’s storm-petrel
Oceanodroma leucorhoa showed that there is
age-specific selection based on telomere length; only
those young birds with the longest telomeres survive to
old age (Haussmann et al., 2008b). Given these findings,
variation in telomere length likely decreases with ad-
vancing age in a population as those individuals with the
shortest telomeres die. In studies focusing only on the
oldest subset of individuals there may not be enough
variability in telomere length to see a clear pattern with
survival or no relationship may exist between telomere
length and survival in this biased subset of the population.
3.2 Telomeres and lifespan
We know very little about physiological constraints
on the evolution of life-history traits in general, and, in
particular, about physiological and molecular adjust-
ments that accompany the evolution of variation in life-
span (Ricklefs et al., 2002). Elucidating factors that in-
fluence lifespan in wild populations, especially those
that may mediate life history trade-offs, is a major focus
of evolutionary ecology. One such factor may be te-
lomeres, and one might expect that particularly
long-lived species would have relatively long telomeres.
To date, there is only one phylogenetically-controlled
HAUSSMANN MF, MARCHETTO NM: Telomeres, stress and survival 719
study exploring telomere length and lifespan. In a com-
parison of 15 rodent species, no relationship was found
between telomere length and lifespan (Seluanov et al.,
2007). In addition, laboratory mice vary widely in their
telomere lengths (10 kb!200 kb; Kipling et al., 1990;
Hemann et al., 2000), although this variation does not
correlate with lifespan differences. Jemielity et al.,
(2007) explored the relationship between telomere
length and lifespan in ants Lasius niger, a species with
markedly different lifespan in different castes. While
long-lived queens (up to 28 years) have longer te-
lomeres then short-lived males (2–3 months), there is no
difference in telomere length between queens and
workers (1–3 years).
Although absolute telomere length might not explain
differences among species in longevity, the rate at which
telomere erosion occurs might be more important. One
study explored how the rate of telomere shortening is
related to interspecific variation in lifespan. In a com-
parison of 5 avian species, the rate of telomere shorten-
ing is inversely related to maximum lifespan;
shorter-lived species show greater telomere loss per year
than longer-lived species (Haussmann et al., 2003b).
Subsequent work has been consistent with the pattern as
long-lived great frigatebirds Fregeta minor; (Juola et al.,
2006) and northern fulmars Fulmarus glacialis
(Haussmann et al., 2008a), have much slower loss rates
than short-lived species. A survey of the mammalian
literature also demonstrates a relationship between the
rate of telomere shortening and lifespan (Haussmann et
al., 2003b). Further comparative work is needed to de-
termine whether this pattern holds in other taxa, but
given the variable length of the g-strand overhang and
size of the t-loop in different species (Aubert et al.,
2008), it seems that both absolute length of telomeres
and the rate at which they shorten is important in the
accumulation of critically short telomeres and cellular
senescence (Haussmann et al., 2008a).
Comparative work exploring the relationship be-
tween telomerase and lifespan among species is also
increasing. Because telomerase activity allows for
unlimited cellular proliferation, long-lived organisms
are thought to down-regulate telomerase at early devel-
opmental stages as a tumor-protective mechanism
(Wright et al., 2001; Djojosubroto et al., 2003). A com-
parison between mice and humans does in fact show
that humans down-regulate telomerase in most tissues
whereas telomerase activity is high in many rodent tis-
sues (Forsyth et al., 2002). However, telomerase activity
in other domesticated animals has shown no clear pat-
tern with lifespan, with some species showing hu-
man-like patterns (horses - Argyle et al., 2003; sheep -
Cui et al., 2003) (domestic cats - McKevitt et al., 2003)
(domestic dogs - Nasir et al., 2001), and other species
have telomerase profiles more similar to laboratory
mice (pigs - Fradiani et al., 2004).
A phylogenetically controlled comparison of telom-
erase activity in 15 rodent species showed that telom-
erase activity does not coevolve with lifespan but in-
stead coevolves with body mass; larger rodents appear
to repress telomerase activity in somatic cells (Seluanov
et al., 2007). In mammals, this suggests that body mass,
and not lifespan presents a greater cancer risk, and large
mammals evolve repression of telomerase activity to
mitigate that risk. Alternatively, in four species of birds,
telomerase was measured in a variety of tissues at three
ages and the longest-lived species tended to have the
highest telomerase activities regardless of body mass
(Haussmann et al., 2007). This suggests that telomerase
activity in bone marrow may be associated with the rate
of telomere loss in birds; birds with lower rates of te-
lomere loss and longer lifespans have higher bone mar-
row telomerase activity throughout life. More compara-
tive work in broader taxonomic groups that control for
phylogeny is needed to examine the pattern between
telomerase, body mass, and lifespan; and whether dif-
ferences in telomerase activity impacts telomere loss
and survival.
4 Physiological Stress: The
Glucocorticoid Stress Response
Environments are unpredictable, and the ability to
acclimate to an ever-changing environment to maintain
homeostatic balance is advantageous. For organisms in
natural populations, environmental stressors such as
temperature change, food scarcity, and predators are
particularly important. The vertebrate “stress response”
is a suite of integrated physiological response mecha-
nisms regulated primarily by the endocrine system,
which allows organisms to cope with stressors. The
cascade of hormones released during a stress response
prompt a reallocation of resources to physiological proc-
esses and behaviors that maximize chances of survival.
Two of the major hormone classes involved are cate-
cholamines, including epinephrine and norepinephrine,
and steroid glucocorticoid hormones (GCs), such as cor-
tisol and corticosterone. Secretion of these hormones is
regulated in part by a negative feedback system. Both
physical and psychological conditions at the time of acti-
vation of the stress response impact an organism’s re-
720 Current Zoology Vol. 56 No. 6
sponse; thus the physiological state of the organism must
be taken into account when evaluating the levels of stress
(McEwen et al., 2003; Romero 2004).
The Hypothalamic-Pituitary-Adrenal (HPA) axis is
responsible for the secretion of glucocorticoids. In eco-
logical studies, the release of glucocorticoids is the most
common metric used to measure the stress response.
Glucocorticoids act to mobilize energy stores and also
to inhibit other physiological systems (e.g reproduction,
immune function, growth) in order to conserve energy
during the stress response. Glucocorticoids also act on
the brain to increase appetite and to increase locomotor
activity and food-seeking behavior, thus regulating be-
haviors that control energy intake and expenditure
(McEwen et al., 2003). To maintain normal physiologi-
cal function, glucocorticoids are secreted at a baseline
level, although there is currently controversy whether
baseline levels of glucocorticoids are a reliable indicator
of organismal fitness (Bonier et al., 2009). During stress,
glucocorticoid secretion increases in part to mobilize
more metabolic fuel to cope with the stressor, and once
the stress is overcome glucocorticoids return to a base-
line level. While the immediate stress response provides
significant benefits in the short-term, the stress response
may be detrimental and even fatal if activated for the
long-term (Sapolsky et al., 2000). Long-term oversecre-
tion of glucocorticoids is referred to as chronic stress
(McEwen et al., 2003; Romero, 2004). Repetitive chal-
lenges to homeostatic balance, for example in the form
of environmental irritants, poor health, social status,
unpredictable environments, or work-induced anxiety in
humans result in chronic stress, although the degree to
which animals experience chronic stress in the wild is
unclear (Goymann et al., 2004).
One idea that has permeated gerontology for a cen-
tury is that physiological stress accelerates the aging
process. Organismal aging is broadly defined as a set of
cumulative, progressive, intrinsic, deleterious changes
that result in damage to cells and tissues. Over time this
“wear and tear” results in increased mortality. In this
way, aging accommodates theories of stress physiology,
which hypothesizes that risk of disease can be increased
and exacerbated by prolonged exposure to psychologi-
cal or physical challenges (Sapolsky, 2004). To better
elucidate the link between physiological stress and oxi-
dative stress, Epel et al. (2004) connected data on
chronically stressed individuals with measures of oxida-
tive stress and telomere shortening. They found that
women with higher levels of stress, by both an objective
and subjective measure, had shorter telomeres, lower
telomerase activity, and higher oxidative stress com-
pared with women with lower levels of stress (Fig. 2).
This suggested physiological stress may directly influ-
ence premature cellular senescence as the lymphocytes
of the stressed woman had aged an equivalent of 9–17
more years based on telomeres loss in comparison to the
low stress woman (Epel et al., 2004).
Fig. 2 Telomere length and telomerase activity of
mother’s with either a healthy child or a chronically ill
child
Mother’s of chronically ill children were more likely to have high
perceived stress scores while mothers of healthy children were more
likely to have low perceived stress scores. A. Average telomere length
and SE. B. Average telomerase activity and SE. The high-stress group
had shorter telomeres and lower telomerase activity even after con-
trolling for age and BMI. (Reproduced from Epel et al., (2004) with
permission of Copyright (2004) National Academy of Sciences,
U.S.A.)
5 Linking Stress Hormones with Oxi-
dative Stress and Telomeres
Identifying the mechanisms underlying variation in
survival provides important insight into the evolution
of life history strategies and phenotypic variation in
longevity. Glucocorticoids are often employed as indi-
HAUSSMANN MF, MARCHETTO NM: Telomeres, stress and survival 721
ces of physiological condition or individual fitness
(Wikelski et al., 2006; Bonier et al., 2009), although
there is conflicting evidence connecting organismal
survival as a consequence of either an acute stress re-
sponse (Breuner et al., 2008) or baseline glucocorti-
coid levels (Bonier et al., 2009). While glucocorticoids
are sure to impact organismal survival in a number of
ways, the recent biomedical evidence linking eleva-
tions in stress hormones with elevated oxidative stress
presents a new model of one way that glucocorticoids
may impact survival. Here, we present a conceptual
model that explores the links among the glucocorticoid
stress response, oxidative stress, telomere dynamics,
and survival (Fig. 3).
Fig. 3 Proposed connections among the glucocorticoid
stress response, oxidative stress, telomere dynamics, and
survival
At the center of the model are two gray rectangles representing oxida-
tive stress and telomere dynamics. Oxidative stress is the balance
between free radical generation, antioxidant defense and oxidative
damage repair. These three mechanisms determine the current level of
oxidative damage (dark arrows and boxes show a positive effect while
white arrows and boxes show a negative effect). Telomere dynamics is
the sum of telomere loss mechanisms, the end-replication problem and
free radical damage, and telomere maintenance mechanisms, like the
enzyme telomerase. These mechanisms determine the current telomere
length (dark arrows and boxes show a positive effect while white
arrows and boxes show a negative effect). Both high levels of oxida-
tive damage and short telomeres are thought to decrease survival
(white arrows moving out to the right of the gray rectangles showing a
negative effect on survival). Recent evidence suggests glucocorticoids
modulate telomere dynamics and oxidative stress (arrows moving into
the left of the gray rectangles – gray arrows represent unknown or
tentative relationships). Glucocorticoids may impact oxidative stress
by altering free radical generation (arrow 1), antioxidant defense (ar-
row 2), or oxidative damage repair (arrow 3). Glucocorticoids may
impact telomere length by altering cell division (arrow 4) or telomere
maintenance (arrow 5).
There is increasing evidence that oxidative stress
and telomere dynamics are important in mediating life
history trade-offs. The underlying regulation of both of
these processes has been well studied over the past few
decades and remains a hotbed of current research. This
work was briefly reviewed in the first part of this con-
tribution and is summarized by the central gray rec-
tangles in Fig. 3. Notice that while telomere dynamics
and oxidative stress are separate processes, some me-
diators of oxidative damage also impact telomere
shortening, and thus, telomere length can be viewed as
an integrative measure of both telomere dynamics and
oxidative stress. Both oxidative stress and telomere
dynamics are thought to influence survival (Fig. 3,
arrows leaving the right side of the central gray rec-
tangles), and in this review we concentrated specifi-
cally on how telomere dynamics relate to aging and
survival in natural populations. Other recent reviews
have concentrated on how oxidative stress relates to
survival in natural populations (Costantini, 2008;
Monaghan et al., 2009).
Perhaps the most intriguing and certainly the most
recent connection has been the relationship between
physiological stress and cellular aging, but we know
relatively little about underlying mechanisms of this
connection (Fig. 3, arrows entering into the left side of
the central gray rectangles). Here we synthesize what is
currently known about how glucocorticoids impact oxi-
dative stress and telomere dynamics. We highlight re-
cent advances that have uncovered important connec-
tions and also point to areas where more data is needed
to determine either the existence or direction of those
connections.
5.1 Glucocorticoids and oxidative stress
Glucocorticoids may have diverse effect on oxidative
stress, and these effects can be summarized in three
main categories: effects on free radical generation (Fig.
3, arrow 1), effects on antioxidant defense (Figure 3,
arrow 2), and effects on oxidative damage repair sys-
tems (Fig. 3, arrow 3).
5.1.1 Glucocorticoid effects on free radicals Early
work by McIntosh and Sapolsky (1996b; 1996a)
showed that the presence of glucocorticoids in rat neu-
ronal cell culture exacerbated the generation of free
radicals. Since that time, there have been a growing
number of studies both in rodents (Liu et al., 1999;
Kotrschal et al., 2007) and humans (Cernak et al., 2000;
Irie et al., 2001; Irie et al., 2003; Epel et al., 2006;
Simon et al., 2006; Damjanovic et al., 2007) that find a
connection between glucocorticoids and oxidative
722 Current Zoology Vol. 56 No. 6
stress. Other taxa have received less attention, al-
though domestic chickens (Gallus gallus domesticus,
Lin et al., 2004) and captive kestrels (Falco tinnuncu-
lus, Costantini et al., 2008) both show an increase in
oxidative damage markers after chronic exposure to
glucocorticoids.
The majority of studies infer glucocorticoids effects
on oxidative stress by measuring oxidative damage, and
this probably reflects the inherent difficulty in the direct
measurement of free radicals because of their intrinsic
reactivity and short half-lives (Monaghan et al., 2009).
However, recent in vitro work has shown that blocking
the glucocorticoid receptors via RU486, a glucocorti-
coid receptor antagonist, also blocks the glucocorti-
coid-mediated rise in free radical production suggesting
that glucocorticoids regulate genes involved in free
radical generation (You et al., 2009). We do not know
the nature of these genes however, and more effort is
needed to determine whether they alter free radical
generation through increasing mitochondrial respira-
tion rate or changing the proton-motive force across the
membrane.
5.1.2 Glucocorticoids effects on antioxidant defense
Glucocorticoids may promote oxidative stress by dis-
abling either enzymatic antioxidants or dietary anti-
oxidants. The effects of glucocorticoids on enzymatic
antioxidants have been the best studied, and in many
cases glucocorticoids decreases enzymatic antioxidant
activity (Liu et al., 1999). However, other work has
highlighted a more complex relationship between
stress hormones and antioxidants then first imagined.
Long-term in vivo supplementation of glucocorticoids
in rats caused a decrease in Cu/Zn superoxide dismu-
tase in the brain but an increase in the liver, while
catalase was unaffected in the brain, but decreased in
the liver (McIntosh et al., 1998). In another case, acti-
vation of the glucocorticoid receptor by hydrogen
peroxide in vitro results in overexpression of the anti-
oxidant thioredoxin (Makino et al., 1996), reiterating
that antioxidant activity isn’t only decreased in the
presence of glucocorticoids. The effect of glucocorti-
coids on dietary antioxidants has received less study,
and it is not known whether glucocorticoids affect the
absorption of these important molecules. Even so, ad-
ministration of either enzymatic or dietary antioxidants
with glucocorticoids appears to have a protective effect
on glucocorticoid-induced oxidative damage (Liu et al.,
1999; Herrera et al., 2010). For example, while gluco-
corticoid treatment in newborn rats had detrimental
effects on survival, the coadministration of glucocor-
ticoids with either vitamin C or vitamin E improved
survival, possibly by alleviating enhanced free radical
production by glucocorticoids. Thus, the overall effect
of glucocorticoids on antioxidant activity appears to be
both situation and tissue dependent. Some of this
variation is likely not only due to differences in the
types and doses of glucocorticoids used, but also be-
cause glucocorticoids themselves serve different func-
tions in different tissues or at different doses and dura-
tions of exposure. We also need a better understanding
of whether upregulation of enzymatic antioxidants is a
result of the glucocorticoids themselves or a response
to glucocorticoid-mediated increases in free radical
generation.
5.1.3 Glucocorticoids effects on oxidative damage
repair systems There have been far fewer studies
exploring the link between glucocorticoids and oxida-
tive damage repair mechanisms (Fig. 3, arrow 3). While
some studies report that psychological stress impairs the
repair of oxidative damage, very few have specifically
examined the effects of glucocorticoids (Gidron et al.,
2006). Recently, in vitro work showed that short-term
exposure to glucocorticoids induced a five-fold in-
crease in DNA damage and pre-treatment with RU486
eliminated this increase. Interestingly, the glucocorti-
coids specifically interfered with DNA repair mecha-
nisms in the cell (Flint et al., 2007). Taken together,
research exploring the effects of glucocorticoids on
antioxidants and repair suggests that a critical part of
glucocorticoid-induced oxidative damage is through
inhibition of these defense pathways. More work in
these relatively understudied areas promises to un-
cover new insight into how physiological stress im-
pacts cellular aging.
5.2 Glucocorticoids and telomere dynamics
While the majority of the studies on the relationship
between glucocorticoids and oxidative stress have fo-
cused on measuring oxidative damage, in a similar way,
the majority of the studies on the relationship between
glucocorticoids and telomeres have focused on meas-
uring telomere length. But like oxidative stress, glu-
cocorticoids may impact telomere in diverse ways.
These can be summarized in three main categories:
effects on telomere length through increasing free
radical generation (Fig. 3, central gray rectangles),
effects on cell division and the end-replication problem
(Fig. 3, arrow 4), effects on telomere maintenance (Fig.
3, arrow 5). The first of these three categories has been
covered above, and the other effects will be summa-
rized below.
HAUSSMANN MF, MARCHETTO NM: Telomeres, stress and survival 723
The pioneering work of Epel and colleagues (2004)
established that chronic stress resulted in an increased
rate of telomere shortening and decreased telomerase
activity (Fig. 2). Further work showed that elevated
glucocorticoids were related to the negative effects on
telomeres, suggesting that stress hormones mediate the
destructive effect of stress on telomere maintenance
(Epel et al., 2006). This work has been correlative and
studies exploring the mechanistic links between gluco-
corticoids and telomere regulation have been limited.
One intriguing possibility is that glucocorticoids shorten
telomeres by increasing cell proliferation and the resul-
tant end-replication problem. While glucocorticoids
have been linked to apoptosis in certain tissues their role
as a mitogen is less clear (Clark et al., 2003) and the
link between glucocorticoids and cell division awaits
further study. Recently, however, one potential mecha-
nism linking glucocorticoids and telomere loss was
proposed. Chronic exposure to cortisol in vitro down-
regulates telomerase activity in activated human T
lymphocytes. Specifically, this effect is caused by a re-
duction in the transcription of TERT, the catalytic com-
ponent of telomerase (Choi et al., 2008), and it may be
that elevated glucocorticoids hasten telomere loss
through this mechanism.
6 Conclusions
As the number of studies increase on the connection
between glucocorticoids, oxidative stress and telomere
dynamics the relationships become more complex. That
complexity serves as an interesting puzzle that invites
more study. Rodent and human studies connecting stress
to cellular aging are steadily increasing, but the taxo-
nomic breadth of these types of relationships is cur-
rently unknown. For example, only one study to date
has explored physiological stress and telomeres in
non-human animals. Male and female wild-caught mice
Mus musculus that were exposed to overcrowding stress
had shorter telomeres than mice that were not stressed
(Kotrschal et al., 2007). While these studies have helped
to establish an interesting pattern, they often don’t
measure stress hormones or explore underlying mecha-
nisms (Epel et al., 2004; Kotrschal et al., 2007; Tyrka et
al., 2010). As we move forward in this fascinating field
we need to continue to probe the causal link between
glucocorticoids and cellular aging, and we need much
more data on non-human animals and rodents, particu-
larly those from natural populations.
The literature on the glucocorticoid stress response in
natural populations is vast (Breuner et al., 2008; Bonier
et al., 2009), while work on oxidative stress and te-
lomeres in natural populations are just now beginning to
accumulate (Haussmann et al., 2005; Monaghan et al.,
2009; Salomons et al., 2009). We need to better under-
stand how the glucocorticoid stress response is mecha-
nistically linked to increased oxidative stress and te-
lomere dynamics. In natural settings, linking the
well-established study of stress hormones to the rela-
tively new study of oxidative stress and telomere dy-
namics promises to provide answers to many interesting
questions:
- Are populations in chronically stressful environ-
ments experiencing higher mortality due to an increase
in oxidative damage and short telomeres?
- Life history trade-offs in general may be mediated
in part by stress’s effects on cellular aging. If increased
investment into reproduction is partially accomplished
through an increase in glucocorticoids, is this paid off in
the long-term by decreased survival?
- Maternal allocation of glucocorticoids to the de-
veloping fetus or to the yolk in oviparous species may
signal a stressful environment and result in offspring
with a thrifty phenotype. Are the long-term costs of this
thrifty genotype a hyperactive stress response and in-
creased cellular aging?
- Stress has profound effects on immune function.
Are some of those effects mediated by oxidative stress
and telomere dynamics? For example, does chronic
stress result in the rapid loss of telomeres leading to
fewer possible cellular divisions of T lymphocytes and
eventual immunosenescence?
These questions just begin to scratch the surface of
how a better understanding of stress and cellular aging
can shed light on important ecological questions. If the
link between the glucocorticoid stress response and
oxidative stress and telomeres is established in natural
populations, it ties together two fields long thought to
be important to organismal survival: stress physiol-
ogy and aging biology. Establishing this integrative
link will require continued collaboration between the
biomedical community and physiological ecologists.
Doing so would examine how physiological trade-offs
are explained at the molecular level and shed light on
how environmental perturbation impacts life history
trajectories.
Acknowledgements We thank Morgan Benowitz-Fredericks
for valuable discussion, Robert Mauck for helpful comments,
three anonymous reviewers for constructive criticism, and
NSF support to MFH.
724 Current Zoology Vol. 56 No. 6
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